Mitochondrial ATP Synthase in Cardiac Biology and Disease

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We have created two independent mouse models of adult cardiomyocyte-specific mitochondrial ATP synthase deficiency: cardiomyocyte-specific ATP5L knockout (KO) mice and cardiomyocyte-specific ATP5J KO mice. Analysis of both models have shown that mice with ~90% depletion of the mitochondrial ATP synthase unexpectedly remain healthy with normal cardiac function for several weeks before transitioning to lethal heart failure with reduced ejection fraction (HFrEF). Studies in the parent grant are investigating the compensatory mechanisms that maintain cardiac function in the face of severe mitochondrial ATP synthase depletion in cardiomyocytes and the mechanisms that eventually mediate the transition to heart failure which, interestingly, do not appear to involve further deterioration of cardiac energetics. Given the traditional view that the mitochondrial ATP synthesis is essential to sustain energetics in mammalian cells – especially energy- demanding cells such as cardiomyocytes – it is surprising that ~10% of its usual levels in cardiomyocytes are adequate to sustain basal mouse health and cardiac function. Our results suggest that the full complement of mitochondrial ATP synthase in cardiomyocytes is not needed at rest. This observation raises the question as to how much of the mitochondrial ATP synthase is needed in cardiomyocytes to sustain cardiac function under more energetically demanding conditions, a question that could not be previously addressed without these mouse models. To answer this question, it is necessary to impose a physiological stress on the mice that increases the energetic demands of cardiomyocytes – but without simultaneously activating pathological stress pathways. We have chosen to use acute β-adrenergic stimulation with isoproterenol and, independently, acute exercise. A second objective of the Supplement is to deepen our baseline characterization of the ATP5J KO mice, which were generated by the candidate. The baseline characterization of the ATP5L KO mice is already complete. However, studies performed after the parent grant was funded, show that the ATP5J KO mice appear to have an accelerated phenotype. Hence, these mice need a thorough baseline characterization. Thus, the specific aims are: 1. To extend the baseline characterization of the cardiomyocyte-specific ATP5J knockout mice. 2. To assess the response of cardiomyocyte-specific ATP5L KO and ATP5J KO mouse lines to physiological stimuli that increase cardiomyocyte energetic demands. The scientific questions addressed in this Supplement are directly related to those of the parent grant and the resulting information will enhance our understanding of the findings of the parent grant. However, both the proposed work in the Supplement and the personnel required to perform it are distinct from that in the parent grant.